Staphylococcus aureus is a Gram-positive, facultative aerobic bacterium that often colonizes the skin and nose of healthy individuals. The bacterium is considered an opportunistic pathogen and can cause a variety of diseases/conditions in a number of body sites. It is a leading cause of bloodstream, skin and soft tissue and respiratory infections worldwide. The frequency of healthcare and community-associated infections caused by S. aureus has been increasing and efforts to combat these infections have been hampered by the emergence of drug-resistant strains, particularly the methicillin-resistant or MRSA strains.
S. aureus expresses a number of virulence factors (both cell surface expressed and secreted) that aid in bacterial invasion and dissemination in the host. Among the secreted virulence factors are a number of toxins, the most prominent of which is the pore-forming toxin Hemolysin A. S. aureus Hemolysin A is a 33 kDa secreted monomer that oligomerizes into a heptameric structure in the membrane of host cells to form a pore leading to cell lysis, epithelial barrier disruption, inflammation, and tissue damage (Berube et al., (2013), Toxins 5:1140-1166).
Multiple mammalian cell types, including platelets, monocytes, endothelial and epithelial cells, are lysed by Hemolysin A. It has been proposed that one or more of these cell types are the physiologically relevant targets of Hemolysin A rather than red blood cells (RBCs), as human RBCs are susceptible to lysis only when exposed to high concentrations of Hemolysin A (Hildebrand et al., (1991), J. Biol. Chem. 266:17195-17200; Wilke et al., (2010), Proc. Natl. Acad. Sci. USA 107:13473-13478; Berube et al., (2013), Toxins 5:1140-1166).
Hemolysin A has been shown to play a role in pneumonia, dermonecrosis, endocarditis, and sepsis in animal models of S. aureus infection (Tkaczyk et al., (2012), Clin. Vaccine Immunol. 19:377-385, and Kennedy et al., (2010), J. Infect. Dis. 202:1050-1058). S. aureus is a leading cause of skin and soft tissue infections (Moran, et al. (2006), N. Engl. J. Med. 355:666-674)), often causing cellulitis and skin abscesses. In mouse models, active immunization with a non-toxigenic form of Hemolysin A or passive immunization with Hemolysin A-specific antisera or monoclonal antibodies (mAbs) significantly reduces the size of skin lesions and prevents dermonecrosis caused by Hemolysin A-producing S. aureus strains (Kennedy et al., (2010), J. Infect. Dis. 202:1050-1058; Tkaczyk et al., (2012), Clin. Vaccine Immunol. 19:377-385). S. aureus is also a leading cause of pneumonia in hospitalized patients (Kollef et al., (2005), Chest 128:3854-3862 (Erratum in Chest 129:831); Shoff et al., (2006), Grit. Care 10:R97) and has been shown to play a role in mouse models of lung infection (Bubeck Wardenberg et al., (2007), Infect. Immun. 75:1040-1044). Active immunization with a non-toxigenic form of Hemolysin A or passive immunization with Hemolysin A-specific antisera or mAbs significantly reduces morbidity and mortality in mouse models of pneumonia (Bubeck Wardenburg and Schneewind, (2008), J. Exp. Med. 205:287-294; Hua et al., (2014), Antimicrob. Agents Chemother. 58:1108-1117).
Staphylococcus aureus is a leading cause of infection in hospitals and in the community. The emergence of antibiotic-resistant strains of S. aureus such as methicillin-resistant Staphylococcus aureus (MRSA), which are more difficult to treat with standard types of antibiotics, is a current problem in clinical medicine and necessitates the development of new approaches to antibacterial prophylaxis and therapy (Kennedy et al., (2010), J. Infect. Dis. 202:1050-1058).